Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that is often intractable. Elevated nitric oxide (NO) from neuronal and non-neuronal sources in the somatosensory system is implicated in the pathobiology of peripheral neuropathic pain. However, in diabetes, nitrergic nerve degeneration to deplete NO bioactivity appears causal in the pathogenesis of irreversible autonomic neuropathy, another long term complication of diabetes. Hence, this study hypothesized that progressive NO depletion may underpin the pathobiology of PDN and that NO donors may alleviate PDN. Diabetes was induced in rats with intravenous streptozotocin (STZ) at 70 mg/kg and confirmed if blood glucose levels (BGLs) on day 10 post-STZ were ≥15 mmol/L. Analgesic efficacy of subcutaneous (s.c.) bolus doses of the furoxan NO donor, PRG150 was assessed in the STZ-diabetic rat model of PDN at 10-, 14- and 24-weeks post-STZ relative to the sydnominine NO donor, SIN-1 and its prodrug, molsidomine. PRG150 produced dose-dependent analgesia in STZ-diabetic rats whereas SIN-1 and molsidomine evoked neuro-excitatory side-effects, but not analgesia. The 1000-fold larger doses of PRG150 needed to produce analgesia at 14- and 24-weeks (800 pmol/kg) c.f. 10-weeks (8 fmol/kg) post-STZ in rats, suggest that progressive NO depletion is also causal in PDN. Importantly, doses of PRG150 up to 10 000 fold higher than the analgesic dose did not produce hypotension in rats. The 50-fold greater release of NO by SIN-1 c.f. PRG150 in vitro, may underpin the neuro-excitatory rather than analgesic effects of SIN-1/molsidomine. PRG150 is worthy of further investigation as a potential novel analgesic for PDN.

1 On rat isolated pulmonary arteries, vasorelaxation by S-nitrosocaptopril (SNOcap) was compared with S-nitrosoglutathione (GSNO) and nitroprusside, and inhibition by SNOcap of contractions to angiotensin I was compared with the angiotensin converting enzyme (ACE) inhibitor, captopril. 2 SNOcap was equipotent as a vasorelaxant on main (i.d. 2 ± 3 mm) and intralobar (i.d. 600 mm) pulmonary arteries (pIC 50 values: 5.00 and 4.85, respectively). Vasorelaxant responses reached equilibrium rapidly (2 ± 3 min). 3 Pulmonary vasorelaxant responses to SNOcap, like GSNO, were (i) partially inhibited by the soluble guanylate cyclase inhibitor, ODQ (1H-(1,2,4) oxadiazolo(4,3-a)-quinoxalin-1-one; 3 mM) whereas responses to nitroprusside were abolished and (ii) potentiated by hydroxocobalamin (HCOB; NO´free radical scavenger; 100 mM) whereas responses to nitroprusside were inhibited. 4 The relative potencies for pulmonary vasorelaxation compared with inhibition of platelet aggregation were: SNOcap 7 : 1; GSNO 25 : 1; nitroprusside 42000 : 1. 5 SNOcap, like captopril, concentration-dependently and time-dependently increased the EC 50 for angiotensin I but not angiotensin II. The dependence on incubation time was independent of the presence of tissue but diered for SNOcap and captopril. This dierence re¯ected the slow dissociation of SNOcap and instability of captopril, and precluded a valid comparison of the potency of the two drugs. After prolonged incubation (55.6 h) SNOcap was more eective than captopril. 6 Thus, in pulmonary arteries SNOcap (i) possesses NO donor properties characteristic of Snitrosothiols but dierent from nitroprusside and (ii) inhibits ACE at least as eectively as captopril. These properties suggest that SNOcap could be valuable in the treatment of pulmonary hypertension.

The effects of S-nitrosocaptopril (SNOcap), administered either intravenously or by oral gavage, on pulmonary artery pressure (PAP) were examined in anaesthetised normotensive rats and rats with hypoxic pulmonary hypertension (10% oxygen for 1 week). Mean PAP (MPAP) values in hypoxic and normoxic rats were (mmHg) 26 +/- 1.7 and 15 +/- 1.1, respectively. When given intravenously, 1 mg kg(-1) SNOcap reduced MPAP by 28 and 32% in hypoxic and normoxic rats, respectively. The effects of 2 mg kg(-1) were no greater than those of 1 mg kg(-1). Pulmonary vasodepressor responses reached equilibrium in 1.7 +/- 0.18 min following intravenous administration. When given orally 30 min before the measurement of PAP, 30 mg kg(-1), but not 10 mg kg(-1), significantly reduced MPAP in hypoxic rats to 17 +/- 1.5 mmHg. These in-vivo data are consistent with previous in-vitro data showing that SNOcap has direct pulmonary vasorelaxant properties in both large and small pulmonary arteries and also show that SNOcap causes pulmonary vasodepression in the setting of pulmonary hypertension. Since SNOcap also inhibits pulmonary vascular angiotensin converting enzyme (ACE) in pulmonary blood vessels (previous study), it would be an interesting drug with which to assess the benefits of direct pulmonary vasodilatation combined with ACE inhibition (which attenuates pulmonary vascular remodelling) in a long-term study in pulmonary hypertension.